Active immunization with amyloid-β 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system

Active immunization with amyloid-β (Aβ) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, lifethreatening meningoencephalitis. Physiological responses to immunization with Aβ_1-42 are poorly understood. In this study, we characterized cognitive and immunological consequences of Aβ_1-42/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)_35-55/CFA or CFA alone, Aβ_1-42/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aβ_1-42/CFA-immunized animals. In contrast to MOG _35-55/CFA and PBS/CFA controls, the majority of infiltrating cells in Aβ_1-42/CFA-immunized mice were CD11b⁺CD14 ⁺ and CD45^high, indicating their blood-borne monocyte/macrophage origin. Immunization with Aβ_1-42/CFA was significantly more potent than immunization with MOG_35-55/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aβ_1-42-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aβ_1-42/CFA. Thus, this study identifies adjuvant effects of Aβ_1-42, which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aβ immunotherapy.